Scotland is at the forefront of expertise in developing stem cell therapies for leukaemia, yet researchers and clinicians are being challenged by a series of factors that are frustrating the development of the treatments they would like to see for people with life-limiting blood diseases.

In a week that saw Edinburgh host the International Society for Experimental Haematology’s Annual Scientific Meeting, Professor Elaine Dzierzak, Chair of Haematological Regeneration at the University of Edinburgh’s Centre for Inflammation Research, reflects on the need, now more than ever, for healthy blood – and blood research.

Each year, hundreds of patients in Scotland are diagnosed with blood diseases, deficiencies, and cancers (infant and adult leukaemias). These can require drug treatments and/or stem cell transplantations.

In the age of global spread of new viral infections, it is crucial to maintain a healthy blood system, particularly the white blood cells involved in immunity. In addition, as our population ages, there becomes a higher chance of developing blood cancers and red blood cell anaemias. A study of the Lothian Birth Cohort by researchers from the Universities of Glasgow and Edinburgh was published in Nature Medicine this July. This research demonstrates that the accumulation of mutations during aging is a negative fitness factor leading to leukaemia.

How we make billions upon billions of healthy red and white blood cells each day is still a mystery.

It is more than 50 years since the discovery that specialised stem cells are the source of all blood cells in our circulation – knowledge that has contributed to the current bone marrow and cord blood clinical transplantation therapies for patients with red and white blood cell deficiencies, diseases, and cancers.

The challenge

Yet, in 2022 we are still unable to provide cures for all patients suffering from life-threatening blood-related diseases.

This is in part due to the rarity of blood stem cells in bone marrow and umbilical cord blood used in clinical therapies.

There is also a lack of sufficient donations and banked supplies of blood stem cells. Importantly, clinical transplantations of these stem cells require that they be closely matched to the patient’s tissue type to avoid graft rejection.

To date, blood stem cells cannot be newly made or be made to expand to greater numbers when cultured outside the adult bone marrow.

Altogether, these issues have severely limited further clinical therapeutic advancements in transplantation and new drug development and discovery.  

The Institute of Regeneration and Repair

At the University of Edinburgh, 21^st century stem cell strategies are now being realised in the basic medical research laboratories of the Institute of Regeneration and Repair (IRR). A high concentration of leading research scientists are working to solve these problems – to produce sufficient supplies of blood stem cells, red and white cells that will be patient-matched for transplantation therapy and that can be used for patient-specific drug discovery.

The exciting innovative edge at the IRR is based on the early development of these cells. Rather than studying the blood stem cells in adults, my laboratory and the laboratories of Professor Alexander Medvinsky and other IRR researchers are studying normal blood stem cell production during embryonic and foetal stages of development.

Professor Medvinsky’s laboratory found that blood stem cells are produced only during early development (during weeks 4-8 weeks in human gestation) and are produced in sufficient numbers to provide for life-long blood production.

My team was the first to show that blood stem cells are ancestrally-derived from the early vascular cells of the major arteries of the embryo.

Importantly, all this is not happening in isolation, but within a milieu of other non-blood related cells of the developing embryo and foetus – the so-called microenvironmental cell types that support the production and growth of blood cells.

A novel result from Mihaela Crisan’s group has just been published and shows a special growth factor signalling pathway within the cells of the microenvironment is involved in blood stem cell production.

Development not only impinges on normal blood production, but also affects blood cell malignancies such as infant and childhood leukaemias.

Again, the IRR has expert investigators studying how leukaemias develop during early stages of life. In a recent study published in the Cell Reports and Blood journals, Professor Ottersbach’s Edinburgh lab shows the role of the foetal cellular origins on infant leukaemia and has developed a novel model for infant leukaemia that allows drug testing.

Samanta Mariani, a new investigator in the institute is studying the role of macrophages in the normal and malignant microenvironment.

Together, these international leaders in blood development are using innovative single cell technologies to uncover the developmental, cellular and genetic processes giving birth to these important cells.

Making blood

Also at the IRR, the futuristic work on the production of sufficient numbers of blood stem cells and functional cells – such as red blood cells, platelets and macrophages, and moreover patient-specific cells for transplantation therapies – is advancing quickly.

Professor Lesley Forrester is testing new strategies and has already been successful in the production of red blood cells and macrophages. Her use of the latest technologies – including human induced pluripotent stem cells and CRISPR gene editing – is leading to the ever-increasing numbers of functional blood cells that can be generated outside the adult patient.

All this innovative research at the IRR encouraged the International Society for Experimental Hematology Annual Conference to hold its 2022 annual meeting in Edinburgh.

The College of Medicine and Veterinary Medicine together with the IRR blood research community was a pivotal sponsor for this meeting at the Edinburgh International Conference Centre, which took place last week.

Not only did this meeting contribute to local Scottish and global research interest, but with the strengths, scientific excellence and innovations of the local blood research community, this international exposure is expected to bring new vision and attract young investigators to promote blood health research in Scotland. 

 

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